The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the present methods.
Rabies is a viral infection with nearly worldwide distribution that affects principally wild and domestic animals, but also affects humans. The infection causes a devastating and, if untreated, nearly invariably fatal encephalitis. More than 70,000 people die each year from rabies infections, and millions more require post-exposure treatment.
The rabies virus is an enveloped, single-stranded RNA virus of the Rhabdovirus family and Lyssavirus genus. The genome of rabies virus codes five proteins: RNA-dependent RNA polymerase (L); a nucleoprotein (N); a phosphorylated protein (P); a matrix protein (M) located on the inner side of the viral protein envelope; and an external surface glycoprotein (G). The G protein (62-67 kDa) is a type-I glycoprotein composed of 505 amino acids, with two to four potential N-glycosylation sites, of which only one or two are glycosylated depending on the viral strain. The G protein forms protrusions covering the outer surface of the virion envelope and is known to induce the production virus-neutralizing antibodies (See Gaudin et al., 1999).
Rabies infection can be treated or prevented by both passive and active immunizations. Rabies post-exposure prophylaxis (PEP) includes prompt local wound care and administration of both passive (anti-rabies immunoglobulins) and active (vaccines) immunizations. Currently, the anti-rabies immunoglobulins (RIG) are prepared from the serum of either human (HRIG) or equine (ERIG) subjects. The use of immunoglobulins from these sources poses several difficulties, however, including disease transmission, cost, and in the case of equine immunoglobulin, adverse reactions such as anaphylactic shock. To overcome these disadvantages it has been suggested to use monoclonal antibodies capable of neutralizing rabies virus in post-exposure prophylaxis.
Rabies virus-neutralizing murine monoclonal antibodies are known in the art (See Schumacher et al., 1989). However, the use of murine antibodies in vivo is limited due to problems associated with administration of murine antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwanted dramatic immune response against the murine antibody in a human (the “human anti-mouse antibody” (HAMA) reaction). Currently, there is a need for new human rabies virus-neutralizing monoclonal antibodies having improved post-exposure prophylactic potential. It is advantageous that antibodies administered in conjunction with rabies vaccines not interfere with the antigenicity of the vaccine, thereby reducing its efficacy.